Investigators

Principal institution

Background & aims

There are good reasons for thinking of ME/CFS as a disorder of the nervous system. Symptoms such as fatigue, non-refreshing sleep, short-term memory problems, sensitivity to bright light and chemicals, and widespread pain certainly suggest central nervous system involvement. In fact, symptoms consistent with central nervous system pathology were reported with regularity in historical publications on ‘epidemics’ of ME, as Sir Donald Acheson pointed out as long ago as 1959 in his famous review.

There is now good evidence of hypersensitivity of the central nervous system – called central sensitisation – in ME/CFS patients. In fact, its presence would explain much of what we know about the illness, from the influence of infectious agents and immune dysfunctions, to the inability of the brain to activate the normal pathways of pain inhibition during and following physical activity.

However, there is still no direct evidence of central sensitisation; direct monitoring of brain responses to harmful (noxious) stimuli has never been performed in patients with ME/CFS, and such direct evidence is crucial if the scientific world is to be persuaded. For this reason, ME Research UK has funded a consortium of researchers specialising in neurology, cardiology and rehabilitation at Vrije Universiteit Brussel – led by Prof. Jo Nijs who has been at the forefront of ME/CFS investigation for a number of years (see the paragraph at the bottom) – to undertake two related studies. Both aim to unravel the abnormal response of people with ME/CFS to exercise and, specifically, the inability of the brain of these patients to activate pain inhibition during and after physical activity.

The first investigation involves directly monitoring the brain responses of ME/CFS patients to (painful) stimuli, a crucial step if the presence of central sensitisation is to be confirmed. The team will use a laser to provoke responses in the brain (laser-evoked potentials), allowing them to visualise on EEG how the brain processes harmful stimuli. Previous studies have relied on self-reports of pain, but using these objective methods permits the assessment of brain responses independent of the person’s subjective interpretation.

For the study, 20 ME/CFS patients (Fukuda and CCC), 20 people with chronic pain but not ME/CFS (patient control group) and 20 healthy sedentary people will be recruited. Stimuli will be delivered to hand and foot by a CO2 laser, and laser-evoked potentials recorded from two EEG electrodes on the skull. The researchers’ hypothesis is that the size of the laser-evoked potentials will be greater in ME/CFS patients than in the other control groups, a finding which would provide objective evidence of hyperexcitability of the central nervous system in the illness. Interestingly, laser-evoked potentials are currently used in the diagnosis of neuropathic pain, and could become a standard assessment technique in the assessment of ME/CFS too.

The second study will examine blood flow to the brain. A number of previous studies have suggested that blood flow to the brain at rest is reduced in ME/CFS patients. For example, in 1995 researchers found reduced blood flow to the brainstem, and more recent studies have found cerebral blood flow reductions using a variety of techniques, such as arterial spin labeling (2011) or SPECT imaging (2006).

The Belgian researchers intend to examine what happens to flow during exercise; it may be, for example, that changes in blood flow account for the inability of the brain of ME/CFS patients to activate pain inhibition during physical activity. Part of the experiment will involve assessing the contribution of the autonomic nervous system, which has a central role in the regulation of blood flow to the brain. This study will have a randomised, cross-over design, and will include 20 ME/CFS patients and 20 healthy, sedentary and pain-free controls. Each participant will have cerebral blood flow measured in the internal carotid arteries using a colour-coded ultrasound system, with autonomic nervous system monitoring and measurement of pressure pain thresholds. All patients will undergo several dynamic challenges during which the measurements will be taken. These challenges include a Valsalva manoeuvre (a standard test of autonomic function); a submaximal exercise test on a seat ergometer bicycle; and an emotional stressor (to control for the potential complicating effects which emotions can have on physiological measurements). The researchers’ hypothesis is that ME/CFS patients may be unable to increase cerebral blood flow sufficiently during exercise, something that might account for the abnormal pain inhibition processing during and following exercise.

Each of these studies has great potential. If objective testing in the first study finds that pain processing in the brain is impaired, or if the results of the second study show that cerebral blood flow really is impaired in response to exercise and is related to post-exertional malaise and/or dysfunctional pain processing, the hunt will be on to discover the underlying mechanisms in the context of ME/CFS.

Scientific progression at Vrije Universiteit Brussel

The research programme led by Prof. Jo Nijs in Brussels is one of the very few examples, anywhere in the world, of a consistent, on-going, progressive approach to tackling ME/CFS. In most chronic diseases, real breakthroughs come only after years of painstaking work by specialist groups of researchers across the world, so if the scientific enigma(s) of ME/CFS are ever to be solved, the disease must become the main focus of a wide range of investigative programmes like the one in Belgium. Since 2007, the group has received four separate grants from ME Research UK, and have produced a series of scientific papers and reviews showing that, compared with healthy people, ME/CFS patients can have:

Increased sensitivity to pain throughout the body (‘central sensitisation’).

Abnormal central pain processing linked to post-exercise symptoms.

Immune abnormalities with similarities to cancer.

Dysregulation of intracellular immunity which impacts on daily functioning.

Pain after both experimental and ‘self-paced’ exercise, even after 24 hours.

Slower recovery in upper-limb muscle strength after exercise.

Increased oxidative and nitrosative stress.

As Prof. Nijs says, “The funding provided by ME Research UK was of prime importance, helping the work of our ‘Pain in Motion’ research group to expand and helping us to obtain funding from other sources, including the European College for Decongestive Lymphatic Therapy, the Research Foundation Flanders, and the International Association for the Study of Pain (the largest scientific pain society in the world) which awarded a prestigious Early Career Research Grant to Dr. Mira Meeus, ME Research UK Fellow.”